Serotonin (5-hydroxytryptamine or 5-HT), a key transmitter of the peripheral and central nervous system, modulates a wide range of physiological and pathological functions, mediated through a number of receptor families termed 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7. Although the functions of the latter three are less well understood than those of the others, it is generally accepted that compounds which selectively interfere with 5-HT-mediated signal transduction are important novel drug targets.
The rat 5-HT6 receptor was cloned by two different groups (Ruat, 1993; Sebben, 1994), and that of the human, sharing a 89% sequence identity, shortly thereafter (Kohen, 1996). Much of the recent interest in the 5-HT6 receptor is because several psychotropic agents are high affinity antagonists at the human 5-HT6 receptor (Kohen, 1996; Roth, 1994). These compounds include amitriptyline (Ki=65 nM) and the atypical antipsychotics clozapine (Ki=9.5 nM), olanzapine (Ki=10 nM), and quetiapine (Ki=33 nM). None of these compounds, however, is selective. The first selective 5-HT6 receptor antagonists reported are Ro 04-6790 and Ro 63-0563. Their usefulness is limited by their moderate affinity (Ki=50 nM and 12 nM, respectively) and poor pharmacokinetics (Sleight, 1998). With the recent development of the selective 5-HT6 receptor antagonists Ro-04-6790 and SB-271046, there have been several reports on the activity of these compounds in models of cognitive function. SB-271046 improved performance in the Morris water maze (Rogers, 1999). These results are consistent with the finding that chronic intracerebroventricular administration of antisense oligonucleotides directed toward the 5-HT6 receptor sequence led to improvements in some measures of performance in the Morris water maze (Bentley, 1999b). Recently, the effect of 5-HT6 antagonists and 5-HT6 antisense oligonucleotides to reduce food intake in rats has been reported (Bentley, 1997; Bentley, 1999a; Woolley, 2001). Obesity is a condition characterized by an increase in body fat content resulting in excess body weight above accepted norms. Obesity is the most important nutritional disorder in the western world and represents a major health problem in all industrialized countries. This disorder leads to increased mortality due to increased incidences of diseases such as cardiovascular disease, digestive disease, respiratory disease, cancer and type-2 diabetes.
5-HT6 selective ligands have been identified as potentially useful in the treatment or prophylaxis of certain disorders of the central nervous system such as Parkinson's disease, Huntington's chorea and/or schizophrenia, anxiety, depression, manic depression, psychoses, epilepsy, obsessive compulsive disorders, mood disorders, migraine, Alzheimer's disease (enhancement of cognitive memory), age related cognitive decline, mild cognitive impairment, neurodegenerative diseases characterized by impaired neuronal growth, sleep disorders, feeding disorders such as anorexia and bulimia, binge eating disorders, panic attacks, akathisia, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, and pain, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus. 5-HT6 selective ligands are also expected to be of use in the treatment of certain gastrointestinal disorders such as functional bowel disorder and Irritable Bowel Syndrome and in the treatment or prophylaxis of obesity and type-2 diabetes, to achieve reduction of body weight and of body weight gain. The reduction of body weight and of body weight gain (e.g. treating body-weight disorders) is achieved inter alia by reduction of food intake.
The goal of the present invention was to provide potent and selective 5-HT6 antagonists, metabolically more stable than known, chemically related, 5-HT6 antagonists (as disclosed in WO 2008/034863), compounds useful for the treatment of certain CNS disorders.
Surprisingly it was found that certain arylsulfonyl pyrazoline carboxamidine derivatives bearing a H-bond donor functionality on or in the arylsulfonyl moiety, are 5-HT6 receptor antagonists, more potent, and metabolically more stable than known, chemically related, 5-HT6 antagonists. The invention relates to a compound of the general formula (1):
                or a tautomer, stereoisomer, N-oxide, or a pharmacologically acceptable salt of any of the foregoing, wherein:        R1 is chosen from hydrogen or an alkyl(C1-4) group, optionally substituted with one or more halogen atoms or an hydroxyl group,        R2 and R3 are independently chosen from hydrogen, an hydroxyl group or an alkyl(C1-4) group optionally substituted with one or more substituents Q, independently chosen from: halogen, alkyl(C1-4), alkenyl(C1-4), alkynyl(C1-4), CF3, NH2, NHalkyl(C1-4), N[alkyl(C1-4)]2, OH, ═O, O-alkyl(C1-4), or OCF3, or,        R1 and R2, together with the carbon atoms marked ‘a’ and ‘b’ form a C5-8-cycloalkyl ring, optionally substituted with one or more halogen atoms, an hydroxyl group or an alkyl(C1-4) group, or,        R2 and R3, together with the carbon atom marked ‘b’ form a C3-8-cycloalkyl or a C4-8-heterocycloalkyl ring, optionally substituted with one or more substituents Q, as defined above,        R4 and R5 are independently chosen from hydrogen or an alkyl(C1-4) group optionally substituted with one or more substituents Q, as defined above, or,        R4 and R5 are independently chosen from a monocyclic or fused bicyclic aromatic or hetero-aromatic group, optionally substituted with one or more substituents Q, as defined above, with the proviso that Q cannot be ═O (keto) on aromatic rings, or        R3 and R4, together with the carbon atoms marked ‘b’ and ‘c’ form a C3-8-cycloalkyl or a C5-8-heterocycloalkyl ring, optionally substituted with one or more substituents Q, as defined above,        R6 and R7 are independently chosen from hydrogen, or an alkyl(C1-4) group optionally substituted with one or more halogen atoms or an hydroxyl group, or a dialkyl(C1-3)-amino-alkyl(C1-3) group, or,        R6 and R7 independently are chosen from a monocyclic or fused bicyclic aromatic or hetero-aromatic group optionally substituted with one or more substituents Q, as defined above, or,        R6 and R7 independently are a C5-8-cycloalkyl group or a C5-8-heterocycloalkyl group optionally substituted with one or more substituents Q, as defined above, or,        R6 and R7, together with the nitrogen atom to which they are attached, form a C5-8-heterocycloalkyl group optionally substituted with one or more substituents Q, as defined above,        R8 is chosen from:        
wherein:                the asterisk (*) marks the bond to the S-atom,        n is either 0 (zero) or 1,        
                is an aryl or heteroaryl group,        X, Y and Z are independently chosen from C, N, O or S, with the understanding that bonds in the ring containing X, Y or Z can be single or double, and C and N are substituted with H-atoms only,        R and R′ are independently chosen from halogen, alkyl(C1-4), alkenyl(C1-4), alkynyl(C1-4), CF3, NH2, NHalkyl(C1-4), N[alkyl(C1-4)]2, OH, SH, keto, S-alkyl(C1-4), SO-alkyl(C1-4), OCF3, nitro and cyano,        with the proviso that when R1, R3, R4, R5 and R6 are hydrogen, R2 and R7 are ethyl, and R8 is either 4-aminophenyl or 3-chloro-4-aminophenyl, the compounds are not racemic mixtures but pure enantiomers (both racemic mixtures were disclosed in WO 2008/034863).        
The invention relates to racemates, mixtures of diastereomers as well as the individual stereoisomers of the compounds having formula (1). The invention also relates to the E isomer, Z isomer and E/Z mixtures of compounds having formula (1).
The invention particularly relates to a compound of the general formula (1) or a tautomer, stereoisomer, N-oxide, or a pharmacologically acceptable salt of any of the foregoing, wherein:                R1, R4 and R6 are hydrogen        R2 and R3 are independently chosen from hydrogen, an hydroxyl group or an alkyl(C1-4) group, optionally substituted with one or more substituents Q*, independently chosen from: halogen, alkyl(C1-4), NH2, NHalkyl(C1-4), N[alkyl(C1-4)]2 or OH, or        R2 and R3, together with the carbon atom to which they are attached, form a C3-8-cycloalkyl or a C5-8-heterocycloalkyl ring optionally substituted with one or more substituents Q* as defined above,        R5 is chosen from hydrogen or an alkyl(C1-4) group, optionally substituted with one or more substituents Q* as defined above, or a monocyclic aromatic or heteroaromatic group optionally substituted with one or more substituents Q* as defined above,        R7 is chosen from hydrogen, or an unsubstituted alkyl(C1-4) group, optionally substituted with one or more halogen atoms or an hydroxyl group,        R8 is chosen from:        
                wherein the symbols have the same meanings as given in claim 1, with the proviso that when R3 and R5 are hydrogen, R2 and R7 are ethyl, and R8 is either 4-aminophenyl or 3-chloro-4-aminophenyl, the compounds are not racemic mixtures but pure enantiomers.        
In another embodiment the invention relates to compounds of formula (1) wherein either one, or both, of the two potentially asymmetric carbon atoms in the pyrazoline ring is the levorotatory or dextrorotatory enantiomer.
The compounds of the invention of formula (1), as well as the pharmacologically acceptable salts thereof, have 5-HT6 receptor antagonistic activity. They are useful in treating disorders involving 5-HT6 receptors, or treatable by manipulation of those receptors. For instance in: Parkinson's disease, Huntington's chorea, schizophrenia, anxiety, depression, manic depression, psychoses, epilepsy, obsessive compulsive disorders, mood disorders, migraine, Alzheimer's disease, age related cognitive decline, mild cognitive impairment, sleep disorders, eating disorders, anorexia, bulimia, binge eating disorders, panic attacks, akathisia, attention deficit hyperactivity disorder, attention deficit disorder, withdrawal from abuse of cocaine, ethanol, nicotine or benzodiazepines, pain, disorders associated with spinal trauma or head injury, hydrocephalus, functional bowel disorder, Irritable Bowel Syndrome, obesity and type-2 diabetes.
Other embodiments of the invention include:
pharmaceutical compositions for treating, for example, a disorder or condition treatable by blocking 5-HT6 receptors, the composition comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier;
methods of treating a disorder or condition treatable by blocking 5-HT6 receptors, the method comprising administering to a patient in need of such treating a compound of formula (1) or a pharmaceutically acceptable salt thereof;
pharmaceutical compositions for treating, for example, a disorder or condition chosen from the disorders listed herein;
methods of treating a disorder or condition chosen from the disorders listed herein, the methods comprising administering to a patient in need of such treating a compound of formula (1) or a pharmaceutically acceptable salt thereof;
pharmaceutical compositions for treating a disorder or condition chosen from the disorders listed herein, the compositions comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier;
methods for treating a disorder or condition chosen from the disorders listed herein, the methods comprising administering to a patient in need of such treating a compound of formula (1) or a pharmaceutically acceptable salt thereof.
methods of antagonizing a 5-HT6 receptor that comprises administering to a subject in need thereof, an effective amount of a compound of formula (1);
The invention also provides the use of a compound or salt according to formula (1) for the manufacture of medicament.
The invention further relates to combination therapies wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for treating one or more of the conditions listed. Such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the compounds of the invention.
The invention also provides compounds, pharmaceutical compositions, kits and methods for treating a disorder or condition chosen from the disorders listed herein, the method comprising administering to a patient in need of such treating a compound of formula (1) or a pharmaceutically acceptable salt thereof.
The compounds of the invention possess 5-HT6 receptor antagonizing activity. This activity of the compounds of the invention is readily demonstrated, for example, using one or more of the assays described herein or known in the art.
The invention also provides methods of preparing the compounds of the invention and the intermediates used in those methods.
Isolation and purification of the compounds and intermediates described herein can be affected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be taken from the preparations and examples. However, other equivalent separation or isolation procedures could, of course, also be used.
The compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.
Depending on the nature of the various substituents, the molecule can have additional asymmetric centers. Each such asymmetric center will independently produce two optical isomers. All of the possible optical isomers and diastereomers, in mixtures and as pure or partially purified compounds, belong to this invention. The present invention comprehends all such isomeric forms of these compounds. Formula (1) shows the structure of the class of compounds without preferred stereochemistry. The independent syntheses of these diastereomers, or their chromatographic separations, may be achieved as known in the art by appropriate modification of the methodology disclosed therein. Their absolute stereochemistry may be determined by the X-ray crystallography of crystalline products or crystalline intermediates, which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. Racemic mixtures of the compounds can be separated into the individual enantiomers by methods well-known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling often consists of the formation of salts using an enantiomerically pure acid or base, for example (−)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases: Methods well-known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well-known in the art.
Cis and trans isomers of the compound of formula (1), or a pharmaceutically acceptable salt thereof, also belong to the invention, and this also applies to tautomers of the compounds of formula (1) or a pharmaceutically acceptable salt thereof.
Some of the crystalline forms for the compounds may exist as polymorphs: as such intended to belong to the invention. In addition, some of the compounds may form solvates with water (i.e. hydrates), or common organic solvents. Such solvates also fall within the scope of this invention.
Isotopically-labeled compound of formula (1) or pharmaceutically acceptable salts thereof, including compounds of formula (1) isotopically-labeled to be detectable by PET or SPECT, also fall within the scope of the invention. The same applies to compounds of formula (I) labeled with [13C]—, [14C]—, [3H]—, [18F]—, [125I]— or other isotopically enriched atoms, suitable for receptor binding or metabolism studies.
The compounds of the invention may also be used as reagents or standards in the biochemical study of neurological function, dysfunction and disease.